Enantiopure sulfones, e.g. of the formula R.sup.1 --CHX--CHR.sup.3 --SO.sub.2 R.sup.2 (1), are of interest as synthetic building blocks, for example, as intermediates in the preparation of enantiopure hydroxamic acids which are under investigation as MMP inhibitors, as described in, inter alia, WO-A-9805635. The enantiopure hydroxamic acids may be prepared by resolution of an intermediate; however, resolution processes are inefficient, with a maximum yield 50% of the correct enantiomer being obtainable. For drug manufacture, an asymmetric synthesis which provides a single enantiomer is often more attractive.
3-Substituted 2-sulfonylmethylpropionic acids have been prepared in moderate e.e. (enantiomeric excess), i.e. up to around 80% e.e. in two steps, from the corresponding allyl sulfides, by sequential asymmetric hydrogenation and oxidation at sulfur (DE-A-4233100; Jendralla, Tetrahedron: Asymmetry (1994) 5:1183-1186; Beck et al, Tetrahedron (1994) 50:4691-4698; Jendrella, Proceedings of Chira Tech '97 (The Catalyst Group). The requisite allyl sulfides are normally prepared as E/Z mixtures by a Wittig olefination reaction; subsequent separation of geometric isomers is required to give optimum results in the asymmetric hydrogenation process. For example, (E)-2-tert-butylthiomethyl-3-(1-naphthyl)acrylic acid was hydrogenated in methanol using a catalyst prepared from (S)-(-)-BINAP, benzeneruthenium (II) chloride dimer and NaOAc at 150.degree. C. and 13800 kPa (2000 psi), followed by peracid oxidation to give (S)-3-tert-butylsulfonyl-2-(1-naphthylmethyl)propionic acid. Similar results were achieved via hydrogenation of the corresponding cyclohexylamine salt form. To access (S)-3-tert-butylsulfonyl-2-(1-naphthylmethyl)propionic acid in &gt;99% e.e. required additional processing, with concomitant loss of yield, by crystallisation of diastereomeric salts formed with (R)-1-phenylethylamine.
Homogeneous diastereoselective hydrogenation of (.alpha.-hydroxyalkyl)vinyl sulfones of formula 3 ##STR2##
with an achiral Rh catalyst is known (Ando el al, J. Chem. Soc., Chem. Commun. (1992) 592), giving hydrogenated material in high d.e. This reaction was elaborated by carrying out a kinetic resolution of an (.alpha.-hydroxalkyl)vinyl sulfone using (S,S)-dipamp Rh. The starting (.alpha.-hydroxyalkyl)vinyl sulfone was recovered in 76% e.e. at 50% substrate conversion and 89% e.e. at 57% conversion. The authors indicated that diasteroselectivity is controlled predominantly by coordination of the catalyst to the .alpha.-OH group at the chiral center of the substrated. However, the products have limited utility as synthetic intermediates.
This directing group effect may be akin to that required in asymmetric hydrogenation of other substrate classes. For example, the preparation of .alpha.-amino acids by asymmetric hydrogenation of enamides requires a group such as acetyl (Ac) on the nitrogen, which then has to be removed carefully under conditions giving minimal racemisation at the newly created chiral centre.